Fabien Chauveau

Armed Forces Biomedical Research Institute, France, Bretigny, Île-de-France, France

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Publications (37)99.54 Total impact

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    ABSTRACT: Histamine receptor type 3 (H3) antagonists are promising awakening drugs for treatment of sleep disorders. However, few works have tried to identify their cognitive effects after sleep restriction and their impact on associated neural networks. To that aim, Bl/6J male mice were submitted to acute sleep restriction in a shaker apparatus that prevents sleep by transient (20-40 ms) up and down movements. Number of stimulations (2-4), and delay between 2 stimulations (100-200 ms) were randomized. Each sequence of stimulation were also randomly administered (10-30 s interval) for 20 consecutive hours during light (8 h) and dark (12h) phases. Immediately after 20h-sleep restriction, mice were injected with H3 antagonist (ciproxifan 3mg/kg ip) and submitted 30-minutes later to a working memory (WM) task using spatial spontaneous alternation behavior. After behavioral testing, brains were perfused for Fos immunohistochemistry to assess neuronal brain activation in the dorsal dentate gyrus (dDG) and the prefrontal cortex. Results showed that sleep restriction decreased slow wave sleep (from 35.8 ± 1.4% to 9.2 ± 2.7%, p<0.001) and was followed by sleep rebound (58.2 ± 5.9%, p<0.05). Sleep restriction did not modify anxiety-like reactivity and significantly decreased WM at long (30 s) but not short (5s) inter-trial intervals. Whereas sleep restriction failed to significantly modify immunopositive cells in vehicles, ciproxifan administration prevented WM deficits in sleep restricted mice through significant increases of Fos labelling in prelimbic, infralimbic and cingulate 2 cortex. In conclusion, ciproxifan at 3mg/kg enhanced WM in sleep restricted mice through specific modulation of prefrontal cortex areas.
    Neuropharmacology 05/2014; · 4.11 Impact Factor
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    ABSTRACT: PURPOSE: The purpose of this study was to introduce synchrotron radiation X-ray phase computed tomography (SR-PCT) as a new method of visualizing ultrasmall superparamagnetic particles of iron oxide (USPIO) distribution into the brains of mice with neuroinflammation. PROCEDURES: The sensitivity of the technique was assessed by performing back-to-back SR-PCT and magnetic resonance imaging (MRI) in mice stereotaxically injected with a range of USPIO concentrations. Eight mice with cerebral ischemia were then intravenously injected with USPIOs and imaged back-to-back with MRI and SR-PCT. RESULTS: SR-PCT proved sensitive enough to detect iron in nanomolar quantities. In stroke-induced animals, SR-PCT showed hyperintense areas in the regions of MR signal loss and immunostaining for macrophages. SR-PCT, moreover, identified brain anatomy as clearly as histology, without the need for sectioning or staining, with an examination time of 44 min per brain at an isotropic spatial resolution of 8 μm. CONCLUSION: SR-PCT has potential for cellular imaging in intact brain, with unequaled neuroanatomy.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 04/2013; · 2.47 Impact Factor
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    Molecular Imaging & Biology 01/2013; · 3.10 Impact Factor
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    ABSTRACT: THE INFLAMMATORY RESPONSE FOLLOWING ISCHEMIC STROKE IS DOMINATED BY INNATE IMMUNE CELLS: resident microglia and blood-derived macrophages. The ambivalent role of these cells in stroke outcome might be explained in part by the acquisition of distinct functional phenotypes: classically (M1) and alternatively activated (M2) macrophages. To shed light on the crosstalk between hypoxic neurons and macrophages, an in vitro model was set up in which bone marrow-derived macrophages were co-cultured with hippocampal slices subjected to oxygen and glucose deprivation. The results showed that macrophages provided potent protection against neuron cell loss through a paracrine mechanism, and that they expressed M2-type alternative polarization. These findings raised the possibility of using bone marrow-derived M2 macrophages in cellular therapy for stroke. Therefore, 2 million M2 macrophages (or vehicle) were intravenously administered during the subacute stage of ischemia (D4) in a model of transient middle cerebral artery occlusion. Functional neuroscores and magnetic resonance imaging endpoints (infarct volumes, blood-brain barrier integrity, phagocytic activity assessed by iron oxide uptake) were longitudinally monitored for 2 weeks. This cell-based treatment did not significantly improve any outcome measure compared with vehicle, suggesting that this strategy is not relevant to stroke therapy.
    PLoS ONE 01/2013; 8(6):e67063. · 3.73 Impact Factor
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    ABSTRACT: The present study was aimed at determining the relative contribution of the dorsal (DH) and ventral (VH) hippocampus in stress-induced memory retrieval impairments. Thus, we studied the temporal involvement of corticosterone and its receptors, i.e. mineralocorticoid (MR) and glucocorticoid (GR) in the DH and VH, in relation with the time-course evolution of stress-induced memory retrieval impairments. In a first experiment, double microdialysis allowed showing on the same animal that an acute stress (electric footshocks) induced an earlier corticosterone rise in the DH (15-60 min post-stress) and then in the VH (90-105 min post-stress). The return to baseline was faster in the DH (105 min) than in the VH (120 min). Memory deficits assessed by delayed alternation occurred at 15-, 60-, and 105-min delays after stress and were closely related to the kinetic of corticosterone rises within the DH and VH. In a second experiment, the GR antagonist RU-38486 and the MR antagonist RU-28318 were administered in the DH or VH 15 min before stress. RU-38486 restored memory at 60 but not at 105 min post-stress delays in the DH, whereas the opposite pattern was observed in the VH. By contrast, RU-28318 had no effect on memory impairments at both the 60- and 105-min post-stress delays, showing that MR receptors are not involved at these delays. However, RU-28318 administered in the DH restored memory when administered at a shorter post-stress delay (15 min). Overall, our data are first to evidence that stress induces a functional switch from the DH to VH via different corticosterone time-course evolutions in these areas and the sequential GR receptors involvement in the DH and then in the VH, as regards the persistence of stress-induced memory retrieval deficits over time.Neuropsychopharmacology advance online publication, 5 September 2012; doi:10.1038/npp.2012.170.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2012; · 8.68 Impact Factor
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    ABSTRACT: BACKGROUND: Irreversible damage may occur at reperfusion after sustained cerebral ischaemia. AIMS: We investigated the value of cyclosporine A for reducing the infarct size in a model of transient middle cerebral artery occlusion. METHODS: Twenty-seven Sprague-Dawley rats sustained a middle cerebral artery occlusion of one-hour. Acute multimodal Magnetic Resonance Imaging (MRI) was used during occlusion to confirm the success of surgery and measure baseline lesion size. Animals were randomly treated by: (i) intracarotid cyclosporine A (10 mg/kg) 20 mins before middle cerebral artery occlusion (pretreatment group); (ii) intracarotid cyclosporine A (10 mg/kg) immediately after reperfusion (post-treatment group); and (iii) intracarotid saline immediately after reperfusion. RESULTS: Histopathological measurements on day 1 showed a significant reduction of infarct size in the pretreatment group compared to the post-treatment (percentage values of ipsilateral hemispheres: 16 ± 5% vs. 29 ± 11%, P = 0·004) and saline groups (16 ± 5% vs. 42 ± 12%, P = 0·015). No significant difference was observed between the post-treatment and saline groups (P = 0·065). Behavioural examinations on day 1 showed no significant difference between groups. Immunohistochemistry showed a statistically significant reduction of microglial cell count in the pretreatment group compared to either saline or cyclosporine A post-treatment groups. CONCLUSIONS: We conclude that intracarotid cyclosporine A is effective in reducing infarct size when given prior to ischaemia, but not when administered at reperfusion.
    International Journal of Stroke 08/2012; · 2.75 Impact Factor
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    ABSTRACT: OBJECTIVES: This study sought to evaluate whether the therapeutic effects of an anti-inflammatory drug such as minocycline could be monitored by serial ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI in experimental stroke. METHODS: Mice received a three-dose minocycline treatment (n = 12) or vehicle (n = 12) after permanent middle cerebral artery occlusion. USPIOs were administered 5 h post-surgery. MRI was performed before, 24 h and 48 h post-USPIO administration. MRI endpoints were the extent of signal abnormalities on R2 maps (=1/T2) and quantitative R2 changes over time (∆R2). Post-mortem brains were prepared either for immunohistology (n = 16) or for iron dosage (n = 8). RESULTS: As expected, treatment with minocycline significantly reduced infarct size, blood-brain barrier permeability and F4/80 immunostaining for microglia/macrophages. Areas of R2 maps > 35 ms(-1) also appeared significantly decreased in minocycline-treated mice (ANOVA for repeated measures, P = 0.017). There was a fair correlation between these areas and the amount of iron in the brain (R(2) = 0.69, P = 0.010), but no significant difference in ∆R2 was found between the two groups. CONCLUSIONS: This study showed that the extent of signal abnormalities on R2 maps can be used as a surrogate marker to detect minocycline effects in a murine experimental model of stroke. KEY POINTS : • Ultrasmall superparamagnetic particles of iron oxide offer new avenues for MRI research • Treatment of the inflammatory response following ischaemic stroke is currently undergoing evaluation. • Minocycline treatment significantly reduced areas of signal abnormalities on USPIO-enhanced MRI. • These areas correlated with the amount of iron in the brain. • Thus USPIO-enhanced MRI might provide a surrogate marker to monitor treatment.
    European Radiology 07/2012; · 4.34 Impact Factor
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    ABSTRACT: The broad aim underlying the present research was to investigate the distribution and homing of bone marrow-derived macrophages in a rodent model of transient middle cerebral artery occlusion using MRI and ultrasmall superparamagnetic iron oxide (USPIO) to magnetically label bone marrow-derived macrophages. The specific aim was to assess the intra-carotid infusion route for bone marrow-derived macrophage delivery at reperfusion. Fifteen Sprague-Dawley rats sustained 1 h of middle cerebral artery occlusion. USPIO-labeled bone marrow-derived macrophages were slowly injected for 5 min immediately after reperfusion in ischemic animals (n = 7), 1 h after the end of surgery in sham animals (n = 5) and very shortly after anesthesia in healthy animals (n = 3). Multiparametric MRI was performed at day 0, just after cell administration, and repeated at day 1. Immunohistological analysis included Prussian blue for iron detection and rat endothelial cell antigen-1 for endothelium visualization. Intra-carotid cell delivery brought a large number of cells to the ipsilateral hemisphere of the brain, as seen on both MRI and immunohistology. However, it was associated with high mortality (50%). The study of sham animals demonstrated that intra-carotid cell delivery could induce ischemic lesions and may thus favor additional brain damage. The present study highlights severe drawbacks to the intra-carotid delivery of macrophages at the time of reperfusion in this rodent model of transient cerebral ischemia. Multiparametric MRI appears to be a method of choice to monitor longitudinally the effects of cell infusion, allowing the assessment of both cell fate with the help of magnetic labeling and of potential tissue damage. Copyright © 2012 John Wiley & Sons, Ltd.
    NMR in Biomedicine 06/2012; · 3.45 Impact Factor
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    02/2012; , ISBN: 978-953-51-0097-3
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    European Neuropsychopharmacology. 01/2012; 22, Supplement 1:S43-S44.
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    ABSTRACT: Injection of thrombin into the middle cerebral artery (MCA) of mice has been proposed as a new model of thromboembolic stroke. The present study used sequential multiparametric Magnetic Resonance Imaging (MRI), including Magnetic Resonance Angiography (MRA), Diffusion-Weighted Imaging (DWI) and Perfusion-Weighted Imaging (PWI), to document MCA occlusion, PWI-DWI mismatch, and lesion development. In the first experiment, complete MCA occlusion and reproducible hypoperfusion were obtained in 85% of animals during the first hour after stroke onset. In the second experiment, 80% of animals showed partial to complete reperfusion during a three-hour follow-up. Spontaneous reperfusion thus contributed to the variability in ischemic volume in this model. The study confirmed the value of the model for evaluating new thrombolytic treatments, but calls for extended MRI follow-up at the acute stage in therapeutic studies.
    PLoS ONE 01/2012; 7(11):e50083. · 3.73 Impact Factor
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    ABSTRACT: Models of intraluminal middle cerebral artery occlusion present an intrinsic variability in infarct size. Behavioral evaluation is frequently performed during arterial occlusion to confirm success of surgery. AIMS AND/OR HYPOTHESIS: We compared the value of behavioral testing and multimodal magnetic resonance imaging performed during arterial occlusion for identifying successfully operated animals. Rats were tested with behavioral assessment (using three scoring scales and the adhesive removal test) and multimodal magnetic resonance imaging (including magnetic resonance angiography, diffusion-weighted and perfusion-weighted imaging), both performed during the two-hours of middle cerebral artery occlusion using the intraluminal suture model. Behavioral assessment was repeated 24 h after reperfusion, followed by sacrifice. Acute apparent diffusion coefficient lesion volume was correlated with both 2,3,5-triphenyl tetrazolium chloride infarct size (r = 0·75, P = 0·02) and behavioral status (r = 0·66, P = 0·05) on day one. Conversely, no correlation was found between acute behavioral examination and day one outcomes (2,3,5-triphenyl tetrazolium chloride infarct volume, r = 0·40, P = 0·28; behavioral examination, r = 0·39, P = 0·30). Day zero apparent diffusion coefficient volumes (P = 0·04), but not behavioral assessment (P = 0·60), discriminated animals with day one corticostriatal infarcts from these with subcortical infarcts. Acute behavioral testing performed during arterial occlusion fails to identify successfully operated animals. Acute diffusion magnetic resonance imaging may be more appropriate to assess and reduce infarct size variability in this model.
    International Journal of Stroke 12/2011; 7(6):465-72. · 2.75 Impact Factor
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    ABSTRACT: To quantify small amounts of iron-labeled cells in mouse brains with magnetic resonance imaging (MRI). Iron-labeled cells (from 500 to 7,500) were stereotaxically transplanted into the brain of living mice that were subsequently imaged with MRI at 4.7 T. We compared four quantitative methods: (1) T2 relaxometry, (2) T2* relaxometry, (3) the volume of the cloverleaf hypointense artifact generated on T2*-weighted images, and (4) the volume of the cloverleaf hyperintense artifact generated on positive contrast images. The methods based on relaxometry, whether T2 or T2*, did not correlate with the number of injected cells. By contrast, those based on measurement of cloverleaf artifact volume, whether using negative or positive enhancement, showed a significant linear relationship for the given range of cells (R [0.92-0.95], p < 0.05). T2* artifact volume imaging (negative or positive) appears promising for the quantification of magnetically labeled cells following focal injection in the brain.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 08/2011; 13(4):672-8. · 2.47 Impact Factor
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    ABSTRACT: Epidemiologic studies report cardiovascular protection conferred by omega-3 fatty acids, in particular docosahexaenoic acid (DHA). However, few experimental studies have addressed its potential in acute stroke treatment. The present study used multimodal MRI to assess in vivo the neuroprotection conferred by DHA and by a brain-targeting form of DHA-containing lysophosphatidylcholine (AceDoPC) in experimental stroke. Rats underwent intraluminal middle cerebral artery occlusion (MCAO) and were treated at reperfusion by intravenous injection of i) saline, ii) plasma from donor rats, iii) DHA or iv) AceDoPC, both solubilized in plasma. Twenty-four hours after reperfusion, animals underwent behavioral tests and were sacrificed. Multiparametric MRI (MRA, DWI, PWI, T2-WI) was performed at H0, during occlusion, and at H24, before sacrifice. Brain tissue was used for assay of F2-isoprostanes as lipid peroxidation markers. Initial lesion size and PWI/DWI mismatch were comparable in the four groups. Between H0 and H24, lesion size increased in the saline group (mean±s.d.: +18%±20%), was stable in the plasma group (-3%±29%), and decreased in the DHA (-17%±15%, P=0.001 compared to saline) and AceDoPC (-34%±27%, P=0.001 compared to saline) groups. Neuroscores in the AceDoPC group tended to be lower than in the other groups (P=0.07). Treatments (pooled DHA and AceDoPC groups) significantly decreased lipid peroxidation as compared to controls (pooled saline and vehicle) (P=0.03). MRI-based assessment demonstrated the neuroprotective effect of DHA in the MCAO model. Results further highlighted the therapeutic potential of engineered brain-targeting forms of omega-3 fatty acids for acute stroke treatment.
    Current Neurovascular Research 04/2011; 8(2):95-102. · 2.84 Impact Factor
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    ABSTRACT: Epidemiologic studies report cardiovascular protection conferred by omega-3 fatty acids, in particular docosahexaenoic acid (DHA). However, few experimental studies have addressed its potential in acute stroke treatment. The present study used multimodal MRI to assess in vivo the neuroprotection conferred by DHA and by a brain-targeting form of DHA-containing lysophosphatidylcholine (AceDoPC) in experimental stroke. Rats underwent intraluminal middle cerebral artery occlusion (MCAO) and were treated at reperfusion by intravenous injection of i) saline, ii) plasma from donor rats, iii) DHA or iv) AceDoPC, both solubilized in plasma. Twenty-four hours after reperfusion, animals underwent behavioral tests and were sacrificed. Multiparametric MRI (MRA, DWI, PWI, T2-WI) was performed at H0, during occlusion, and at H24, before sacrifice. Brain tissue was used for assay of F(2)-isoprostanes as lipid peroxidation markers. Initial lesion size and PWI/DWI mismatch were comparable in the four groups. Between H0 and H24, lesion size increased in the saline group (mean ± s.d.: +18% ± 20%), was stable in the plasma group (-3% ± 29%), and decreased in the DHA (-17% ± 15%, P=0.001 compared to saline) and AceDoPC (-34% ± 27%, P=0.001 compared to saline) groups. Neuroscores in the AceDoPC group tended to be lower than in the other groups (P=0.07). Treatments (pooled DHA and AceDoPC groups) significantly decreased lipid peroxidation as compared to controls (pooled saline and vehicle) (P=0.03). MRI-based assessment demonstrated the neuroprotective effect of DHA in the MCAO model. Results further highlighted the therapeutic potential of engineered brain-targeting forms of omega-3 fatty acids for acute stroke treatment.
    Current neurovascular research 03/2011; 8(2):95-102. · 3.23 Impact Factor
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    ABSTRACT: Objectives To monitor by magnetic resonance imaging (MRI) intra-carotid injection of labeled macrophages in an animal model of stroke, and to characterize the cellular biotransformation of iron nanoparticles using transmission electron microscopy (TEM).
    Irbm. 01/2011; 32(2):126-129.
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    ABSTRACT: Stroke is the third leading cause of death, after myocardial infarction and cancer, and the leading cause of permanent disability in Western countries. Although anti-inflammatory drugs have shown very promising results in preclinical rodent studies, they appeared to be ineffective against stroke in clinical trials. In this context, non-invasive detection of inflammatory cells after brain ischemia could be helpful (i) to select patients who may benefit from anti-inflammatory treatment, and/or (ii) to target an adequate individualized therapeutic time window. Magnetic resonance imaging (MRI) coupled with injection of iron oxide nanoparticles, a contrast agent taken up by macrophages ex vivo and in vivo, appears to be a promising tool for this purpose. This review focuses on the use of this technique to image inflammation in pre-clinical and clinical studies of stroke. Despite current limitations, MRI of inflammation may become an important tool for the investigation of novel ischemic stroke therapeutics targeting inflammation.
    International journal of clinical pharmacology and therapeutics 11/2010; 48(11):718-28. · 1.20 Impact Factor
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    ABSTRACT: Neuroinflammation is involved in neurological disorders through the activation of microglial cells. Imaging of neuroinflammation with radioligands for the translocator protein (18 kDa) (TSPO) could prove to be an attractive biomarker for disease diagnosis and therapeutic evaluation. The indoleacetamide-derived 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, SSR180575, is a selective high-affinity TSPO ligand in human and rodents with neuroprotective effects. Here we report the radiolabelling of SSR180575 with (11)C and in vitro and in vivo imaging in an acute model of neuroinflammation in rats. The image contrast and the binding of [(11)C]SSR180575 are higher than that obtained with the isoquinoline-based TSPO radioligand, [(11)C]PK11195. Competition studies demonstrate that [(11)C]SSR180575 has high specific binding for the TSPO. [(11)C]SSR180575 is the first PET radioligand for the TSPO based on an indoleacetamide scaffold designed for imaging neuroinflammation in animal models and in the clinic.
    European Journal of Nuclear Medicine 10/2010; 38(3):509-14. · 4.53 Impact Factor
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    ABSTRACT: The key role of neuroinflammation in acute and chronic neurological disorders has stimulated the search for specific radiotracers targeting the peripheral benzodiazepine receptor (PBR)/18 kDa translocator protein (TSPO), a hallmark of neuroinflammation. Here we evaluate the new radiotracer for positron emission tomography (PET) [(18)F]PBR111 in a rodent model of acute inflammation and compare it with [(11)C]CLINME, an (11)C-labelled tracer of the same chemical family, and with the isoquinolinic carboxamide [(11)C]PK11195. We studied radiometabolites by HPLC, in vitro binding by autoradiography and in vivo brain kinetics as well as in vivo specificity of binding using PET imaging. We show that this radiotracer has a high in vitro specificity for PBR/TSPO versus central benzodiazepine receptors, as reflected by the drastic reduction of its binding to target tissue by addition of PK11195 or PBR111, while addition of flumazenil does not affect binding. Only intact [(18)F]PBR111 is detected in brain up to 60 min after i.v. injection, and PET imaging shows an increased uptake in the lesion as compared to the contralateral side as early as 6 min after injection. Administration of an excess of PK11195 and PBR111, 20 min after [(18)F]PBR111 administration, induces a rapid and complete displacement of [(18)F]PBR111 binding from the lesion. Modelling of the PET data using the simplified reference tissue model showed increased binding potential (BP) in comparison to [(11)C]PK11195. [(18)F]PBR111 is a metabolically stable tracer with a high specific in vitro and in vivo binding to TSPO. In addition, considering the longer half-life of (18)F over (11)C, these results support [(18)F]PBR111 as a promising PET tracer of the PBR/TSPO for neuroinflammation imaging.
    European Journal of Nuclear Medicine 05/2010; 37(5):962-72. · 4.53 Impact Factor

Publication Stats

381 Citations
99.54 Total Impact Points

Institutions

  • 2010–2014
    • Armed Forces Biomedical Research Institute, France
      Bretigny, Île-de-France, France
    • Claude Bernard University Lyon 1
      Villeurbanne, Rhône-Alpes, France
  • 2009–2013
    • University of Lyon
      Lyons, Rhône-Alpes, France
    • Université Bordeaux 1
      • UMR CNIC - Centre de Neurosciences Intégratives Cognitives
      Talence, Aquitaine, France
  • 2008–2013
    • French National Centre for Scientific Research
      • Centre de recherche en acquisition et traitement de l'image pour la santé (CREATIS)
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 2008–2010
    • Atomic Energy and Alternative Energies Commission
      • Laboratoire d'Imagerie Moléculaire Expérimentale (LIME)
      Gif-sur-Yvette, Ile-de-France, France
  • 2006–2010
    • Cea Leti
      Grenoble, Rhône-Alpes, France